Humanistic burden of mucopolysaccharidoses: a systematic literature review.

OBJECTIVE: To systematically review the literature and summarize the health-related quality-of-life (HRQoL) of patients undergoing treatment for mucopolysaccharidoses (MPS), a rare, hereditary lysosomal storage disorder. METHODS: A systematic review was performed in accordance with PRISMA guidelines to identify research studies that describe the humanistic burden of MPS. A comprehensive literature search was conducted in EMBASE, MEDLINE, and eligible conferences were screened to include applicable abstracts. RESULTS: Of 870 identified articles, 15 studies reported the HRQoL burden of patients with MPS undergoing or with a history of ERT and/or HSCT. These studies include patients of MPS I (n = 2), MPS II (n = 4), MPS IV (n = 6), MPS VI (n = 1), and subtype not mentioned (n = 2). Although the quality-of-life of MPS patients is influenced by time of diagnosis, pain, cognitive involvement, severity of disease, mobility, dependence, and time of treatment initiation, the HRQoL scores of MPS patients across all the scales were below the median reference population scores across all dimensions. This is seen in comparison to healthy participants but also in comparison to patients with other chronic illnesses. The multi-organ involvement, neurological impairment, pain, and morbidity associated with the condition not only affects activity of daily living but also affects social functioning, emotional status, employment status among adults, and school functioning among children. CONCLUSIONS: This systematic literature review revealed the substantial humanistic burden of individuals affected by MPS as well as caregivers. Significant variation in HRQoL scores was observed, however studies indicate that the quality-of-life of MPS patients is influenced primarily by severity of disease (MPS type and phenotype), and then by time of diagnosis, pain, cognitive involvement, mobility, dependence, and time of treatment initiation. Further studies are needed to assess the global humanistic burden of MPS, particularly in MPS III, VI, VII, and IX subtypes, in adults, and for a longer follow-up period. Considering the vast array of HRQoL assessment tools available and used in this study, researchers should also consider using scales with condition-specific measures to ensure appropriate estimates of effectiveness.

Caregiving for Older Adults With Dementia During the Time of COVID-19: A Multi-State Exploratory Qualitative Study.

This qualitative semi-structured interview study explores how 64 family caregivers for older adults with Alzheimer's Disease and related dementias across eight states experienced and executed caregiving decisions before and during the COVID-19 pandemic. First, caregivers experienced challenges communicating with loved ones and healthcare workers in all care settings. Second, caregivers displayed resilient coping strategies in adapting to pandemic restrictions, finding novel strategies to balance risks while preserving communication, oversight, and safety. Third, many caregivers modified care arrangements, with some avoiding and others embracing institutional care. Finally, caregivers reflected on the benefits and challenges of pandemic-related innovations. Certain policy changes reduced caregiver burden and could improve care access if made permanent. Telemedicine's increasing use highlights the need for reliable internet access and accommodations for individuals with cognitive deficits. Public policies must pay greater attention to challenges faced by family caregivers, whose labor is both essential and undervalued.

Breast Cancer Screening Utilization and Outcomes in Women With Neurofibromatosis Type 1.

INTRODUCTION: Women with neurofibromatosis type 1 (NF1) have up to a 5-fold increased risk for breast cancer before age 50 and a 3.5-fold increased risk of breast cancer overall. The purpose of our study was to assess breast cancer screening utilization and outcomes in this population. PATIENTS AND METHODS: This IRB approved HIPAA compliant study retrospectively assessed consecutive NF1 patients (January 2012-December 2021) with recorded clinical visits and/or breast imaging. Patient demographics, risk factors, and screening mammogram and breast magnetic resonance imaging (MRI) outcomes were recorded. Descriptive statistics were obtained and standard breast screening measures were calculated. RESULTS: One hundred and eleven women (median age 43, range 30-82) were eligible for screening based on current NCCN guidelines. A total of 86% (95/111) of all patients and 80% (24/30) of patients under age 40 had at least 1 mammogram. In contrast, 28% (31/111) of all patients and 33% (25/76) of patients ages 30 to 50 had at least 1 screening MRI. Of 368 screening mammograms performed, 38 of 368 (10%) resulted in the recall, and 22 of 368 (6%) resulted in a biopsy. Of 48 screening MRIs performed, 19 of 48 (40%) short-term follow-ups and 12 of 48 (25%) biopsies were recommended. All 6 screen-detected cancers in our cohort were detected initially on screening mammograms. CONCLUSION: Results confirm the utility and performance of screening mammography in the NF1 population. The low utilization of MRI in our cohort limits the evaluation of outcomes via this modality and suggests there may be an education or interest gap among referrers and patients regarding supplemental screening recommendations.

An Enhanced Recovery After Surgery protocol for robotic-assisted laparoscopic nephrectomies utilizing a quadratus lumborum block.

Enhanced Recovery After Surgery (ERAS) protocols have been developed in several fields to reduce hospitalization lengths and overall costs. There have also been developments in multimodal analgesia methods to curtail opioid usage after surgery. Herein, we present the results of our initiation of an ERAS protocol for robotic-assisted laparoscopic partial and radical nephrectomies, employing a quadratus lumborum (QL) regional anesthetic block. We retrospectively reviewed 614 patients in our Institutional Review Board approved database who underwent robotic-assisted laparoscopic partial or radical nephrectomies from January 2017 to February 2020. An ERAS protocol utilizing multimodal analgesia (acetaminophen and gabapentin) and a QL block was developed and introduced in February 2019. We then compared the opioid consumption and perioperative outcomes of patients before and after ERAS protocol initiation. 192 ERAS patients (February 2019 to February 2020) were compared to 422 non-ERAS patients (January 2017 to January 2019). Baseline characteristics and the proportion of preoperative opioids users were similar between the two groups. There were no statistically significant differences in surgery length, hospitalization length, or complication rates. There were statistically significant differences in our primary endpoint, opioid consumption, on post-operative days 0 (p < 0.001), 1 (p < 0.001), and 2 (p < 0.001). The total opioid requirements over the course of admission were lower in the ERAS group compared to the non-ERAS group (p = 0.03). The initiation of an ERAS protocol employing multimodal analgesia and a QL block, for patients undergoing robotic-assisted laparoscopic partial or radical nephrectomies, can decrease opioid requirements without compromising perioperative outcomes.

Pharmacogenetic testing to guide therapeutic decision-making and improve outcomes for children undergoing anthracycline-based chemotherapy.

Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.

Piriformis syndrome: muscle thickness or volume does not correlate with response to CT-guided injection.

OBJECTIVE: To determine whether size of the piriformis muscle, as characterized by either the coronal width or a segmented volume, correlates with outcomes after CT-guided injections. MATERIALS AND METHODS: A consecutive series of 81 patients with piriformis syndrome received CT-guided injections of the sciatic nerve and piriformis muscle. Volume and thickness measurements of the piriformis were taken from T1W and T2W pre-injection images by two readers. A logistic regression was used to test volume and size effect on first injection response. A cox proportional hazards model was used to evaluate pain-free survival. Identical analyses were performed to test the effects of muscle mass abnormality, nerve abnormality, body mass index, and presence of a split sciatic nerve. RESULTS: There were 15/94 negative responses, 31/94 possible positive responses, and 48/94 positive responses to CT-guided injection. The average pain-free survival time was 38.91 ± 64.43 days. There was no significant correlation of first injection responses with muscle thickness or volume. There was no significant correlation in pain-free survival for muscle thickness or volume. There was no significant correlation in first injection response or pain-free survival with body mass index, muscle abnormalities, nerve abnormalities, or split sciatic nerves. The intraclass correlation was excellent between the two readers for both muscle volume (0.95-0.98) and thickness (0.92-0.97). CONCLUSION: Piriformis muscle volume or thickness did not significantly correlate with post-injection outcome (first injection response and pain-free survival). Thus, if the patient has clinical symptoms of piriformis syndrome, the size of muscle should not determine whether injection is advisable.

Quality of Life in Wilson's Disease: A Systematic Literature Review.

Background: Wilson's disease (WD) is a rare inherited genetic disorder characterized by the progressive accumulation of copper in the brain, liver, and other major organ systems. To date, there have been no comprehensive studies synthesizing evidence pertaining to the quality of life (QOL) in WD. Objective: We conducted a systematic literature review to identify and synthesize the evidence on QOL in patients with WD. Methods: To address this gap in the literature, we conducted a systematic literature review in MEDLINE and EMBASE to identify observational studies and clinical trials reporting QOL outcomes among people living with WD. Results: A total of 442 publications were identified, 41 publications were eligible for full-text screening, and 7 articles, representing 7 studies, met all inclusion criteria. QOL questionnaires used across studies included the 12-Item Short Form Health Survey Questionnaire (version 1) (SF-12) (n=2), the 36-Item Short Form Health Survey Questionnaire (version 1) (SF-36) (n=3), Global Assessment Scale (GAS) (n=1), and World Health Organization QOL brief questionnaire (WHO-QOL-BREF) (n=1). Overall, the pattern in QOL from most studies demonstrated a worse QOL in WD patients compared with the general population, a deterioration in QOL for patients presenting with neurologic symptoms, and more frequent psychiatric symptoms compared with the ones with hepatic symptoms. Discussion: Although our understanding of the underlying pathophysiology of WD has advanced, and novel therapeutics are on the horizon, our understanding of how WD affects overall QOL remains limited. Evidence from this review demonstrates the substantial heterogeneity in reporting outcomes pertaining to the QOL associated with WD. These differences may be attributable to the fact that QOL is not typically assessed and the lack of a standardized method for assessing QOL in WD. Conclusion: This review demonstrates a need for more up-to-date studies with larger sample sizes to further evaluate QOL in patients with WD. The study also demonstrates the need for a WD-specific instrument to measure the QOL in WD patients.

The Impact of Digital Therapeutics on Current Health Technology Assessment Frameworks.

Historically healthcare has been delivered offline (e.g., physician consultations, mental health counseling services). It is widely understood that healthcare lags behind other industries (e.g., financial, transportation) whom have already incorporated digital technologies in their workflow. However, this is changing with the recent emergence of digital therapeutics (DTx) helping to bring healthcare services online. To promote adoption, healthcare providers need to be educated regarding the digital therapy to allow for proper prescribing. But of equal importance is affordability and many countries rely on reimbursement support from the government and insurance agencies. Here we briefly explore how national reimbursement agencies or non-profits across six countries (Canada, United States of America, United Kingdom, Germany, France, Australia) handle DTx submissions and describe the potential impact of digital therapeutics on current health technology assessment (HTA) frameworks. A targeted review to identify HTA submissions and guidelines from national reimbursement agencies or non-profits was conducted. We reviewed guidelines from the Institute for Clinical and Economic Review (ICER) in the USA, the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, the National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK), the Institute for Quality and Efficiency in Health Care (IQWIG) in Germany, Haute Autorité de Santé (HAS) in France, and the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia. Our review identified one set of guidelines developed by NICE in the UK. The guidelines by NICE outlined an evidence standards framework for digital health technologies (DHT). Depending on the organizational impact, financial commitment, and economic risk for the payer, different economic analyses are required. Economic analyses levels are separated into 3 categories, basic, low financial commitment, and high financial commitment. All economic analyses levels require a budget impact analysis. A cost-utility analysis is recommended for DHTs categorized in the high financial commitment category. Whereas, for DHTs that are in the low financial commitment category, a cost-consequence analysis is typically recommended. No HTA guidelines for DTx submissions were identified for the remaining countries (Canada, USA, Germany, France, and Australia).

Changing face of healthcare: digital therapeutics in the management of diabetes.

Diagnosis, prevention, management and treatment of acute and chronic medical conditions have improved with technological advancements in terms of scalability, efficacy, access, and personalized approach. Digital therapeutic applications (DTx) (Blue Star, Diabeo System, Livongo Diabetes Program, Tidepool etc.,) use web-based applications/cloud platforms to provide evidence-based, personalized, rapid point of care management of chronic, behavior-modifiable conditions, including diabetes mellitus (DM). DTx has improved patient compliance, therapeutic success and economic outcomes in DM management by enabling active patient engagement, lifestyle change, comprehensive medical care, and periodic monitoring of glycemic status. Addressing concerns along DTx data vulnerability, comparative efficacy with conventional treatments, ability to accommodate diverse population needs, and resolving ambiguous regulatory policies and reimbursement guidelines are critical for increasing access to DTx, and overcoming availability, accessibility, and affordability issues in the existing resource limited healthcare environment. In this commentary the authors explore the potential, prospects, and challenges of DTx in the management of Diabetes Mellitus.

The RGG domain in the C-terminus of the DEAD box helicases Dbp2 and Ded1 is necessary for G-quadruplex destabilization.

The identification of G-quadruplex (G4) binding proteins and insights into their mechanism of action are important for understanding the regulatory functions of G4 structures. Here, we performed an unbiased affinity-purification assay coupled with mass spectrometry and identified 30 putative G4 binding proteins from the fission yeast Schizosaccharomyces pombe. Gene ontology analysis of the molecular functions enriched in this pull-down assay included mRNA binding, RNA helicase activity, and translation regulator activity. We focused this study on three of the identified proteins that possessed putative arginine-glycine-glycine (RGG) domains, namely the Stm1 homolog Oga1 and the DEAD box RNA helicases Dbp2 and Ded1. We found that Oga1, Dbp2, and Ded1 bound to both DNA and RNA G4s in vitro. Both Dbp2 and Ded1 bound to G4 structures through the RGG domain located in the C-terminal region of the helicases, and point mutations in this domain weakened the G4 binding properties of the helicases. Dbp2 and Ded1 destabilized less thermostable G4 RNA and DNA structures, and this ability was independent of ATP but dependent on the RGG domain. Our study provides the first evidence that the RGG motifs in DEAD box helicases are necessary for both G4 binding and G4 destabilization.

Heterogeneity in renal end points of cardiovascular outcomes trials in Type 2 diabetes.

Composite renal end points and end stage renal disease (ESRD) are frequently included as prespecified secondary end points in the cardiovascular outcomes trials (CVOTs) of diabetes medications. We examined the heterogeneity in the definitions of composite renal end point and ESRD in CVOTs. Five criteria (macroalbuminuria, doubling of serum creatinine, estimated glomerular filtration rate [GFR], ESRD and renal death), were considered for the renal composite end point across the trials. Only three of the 12 trials included all five criteria, whereas the other trials included different combinations of four, three and two criteria. ESRD definition also showed considerable heterogeneity across the trials. Heterogeneity exists in the definitions of renal composite and ESRD end points in CVOTs making it challenging to assess comparative efficacy of the active treatments for reimbursement purposes.

Hydroxyzine Use in Preschool Children and Its Effect on Neurodevelopment: A Population-Based Longitudinal Study.

We identified the first-generation antihistamine hydroxyzine as the earliest and most frequently prescribed drug affecting the central nervous system in children under the age of 5 years in the province of British Columbia, Canada (1. 1% prevalence). Whereas, the antagonism of H1-receptors exerts anti-pruritic effects in atopic dermatitis and diaper rash, animal studies suggest an adverse association between reduced neurotransmission of histamine and psychomotor behavior. In order to investigate hydroxyzine safety, we characterized the longitudinal patterns of hydroxyzine use in children under the age of 5 years and determined mental- and psychomotor disorders up to the age of 10 years. We found significantly higher rates of ICD-9 and ICD-10 codes for disorders such as tics (307), anxiety (300) and disturbance of conduct (312) in frequent users of hydroxyzine. Specifically, repeat prescriptions of hydroxyzine compared to a single prescription show an increase in tic disorder, anxiety and disturbance of conduct by odds ratios of: 1.55 (95%CI: 1.23-1.96); 1.34 (95%CI: 1.05-1.70); and 1.34 (95%CI: 1.08-1.66) respectively in children up to the age of 10 years. Furthermore, a non-significant increased trend was found for ADHD (314) and disturbance of emotions (313). This is the first study reporting an association between long-term neurodevelopmental adverse effects and early use of hydroxyzine. Controlled studies are required in order to prove a causal relationship and to confirm the safety of hydroxyzine in the pediatric population. For the time being, we suggest the shortest possible duration for hydroxyzine use in preschool-age children.

Two Decades of Nursing Home Compare: What Have We Learned?

Approximately two decades ago, federally mandated public reporting began for U.S. nursing homes through a system now known as Nursing Home Compare. The goals were to provide information to enable consumers to choose higher quality nursing homes and to incent providers to improve the quality of care delivered. We conduct a systematic review of the literature on responses to Nursing Home Compare and its effectiveness in meeting these goals. We find evidence of modest but meaningful response by both consumers and providers. However, we also find evidence that some improvement in scores does not reflect true quality improvement, that disparities by race and income have increased, that risk-adjustment of the measures is likely inadequate, and that several key domains of quality are not represented. Our results support moderate success of Nursing Home Compare in achieving intended goals but also reveal the need for continued refinement.

Piriformis syndrome: pain response outcomes following CT-guided injection and incremental value of botulinum toxin injection.

PURPOSE: Piriformis syndrome is a common pain condition affecting the buttock and posterior hip with or without radiation to the leg, and management of the condition involves many treatments. In this study, we hypothesize that a CT-guided injection with botulinum toxin is more effective in providing pain relief than a CT-guided injection without Botox. METHODS: Overall, 97 consecutive patients with piriformis syndrome presented for a CT-guided injection of the piriformis muscle and perineural injection of the sciatic nerve. After the injection, the patients received a visual analog scale pain log to record their pain level until the follow-up appointment. P values of less than 0.2 were considered as confounder and adjusted by inverse probability of treatment weighting (IPTW) via propensity score. The effect of botulinum toxin on 48-hour response and duration of response was tested using weighted chi-square test and weighted Kaplan-Meier analysis. RESULTS: There was a total of 97 patients in the study, and 111 injections, as some patients had bilateral injections. Patients in the Botox group had more 48-hour response than patients in the non-botulinum toxin group (P < 0.001 with IPTW, P = 0.005 without IPTW). Median pain-free survival was 30 days for Botox group and 1 day for non-Botox group (P = 0.059 with IPTW, P = 0.10 without IPTW). CONCLUSION: CT-guided injections with botulinum toxin for patients with piriformis syndrome are more likely to lead to a positive response and a longer duration of response than patients who receive a CT-guided injection without botulinum toxin. We hope that this study facilitates future prospective randomized blind trials for patients with suspected piriformis syndrome.

Poly(A)-Binding Protein Regulates the Efficiency of Translation Termination.

Multiple factors influence translation termination efficiency, including nonsense codon identity and immediate context. To determine whether the relative position of a nonsense codon within an open reading frame (ORF) influences termination efficiency, we quantitate the production of prematurely terminated and/or readthrough polypeptides from 26 nonsense alleles of 3 genes expressed in yeast. The accumulation of premature termination products and the extent of readthrough for the respective premature termination codons (PTCs) manifest a marked dependence on PTC proximity to the mRNA 3' end. Premature termination products increase in relative abundance, whereas readthrough efficiencies decrease progressively across different ORFs, and readthrough efficiencies for a PTC increase in response to 3' UTR lengthening. These effects are eliminated and overall translation termination efficiency decreases considerably in cells harboring pab1 mutations. Our results support a critical role for poly(A)-binding protein in the regulation of translation termination and also suggest that inefficient termination is a trigger for nonsense-mediated mRNA decay (NMD).

Can Standard Health Technology Assessment Approaches Help Guide the Price of Orphan Drugs in Canada? A Review of Submissions to the Canadian Agency for Drugs and Technologies in Health Common Drug Review.

Orphan drugs have high acquisition costs and when standard health technology assessment (HTA) approaches are used to assess their cost-effectiveness, they often appear not cost-effective. The Canadian Patented Medicine Review Board (PMPRB), through new regulations, will apply HTA assessment results from the Canadian Agency for Drugs and Technologies in Health (CADTH) and Institut national d'excellence en santé et en services sociaux (INESSS) when setting the maximum price that can be charged for Category I patented medicines (treatments with an annual cost exceeding 150% of GDP per capita of Canada or with expected annual market size >$50M). Through these regulations, PMPRB has also established a willingness-to-pay threshold of CAD$200,000 or CAD$150,000 per quality adjusted life year (QALY) for medications with a prevalence of no more than 1 in 2000 across all approved indications. We reviewed the orphan drug submissions made to CADTH's Common Drug Review (CDR) January 2015-May 2020 to understand how the methodology of assessing cost-effectiveness of orphan drugs has guided pricing in Canada. A total of 35 orphan drug submissions were assessed by CDR in this period, none of which met the willingness-to-pay threshold of CAD$50,000 per QALY. Only one drug met the CAD$200,000 per QALY for Therapeutic Criteria Level I, and two drugs met CAD$150,000 per QALY for other Therapeutic Criteria Levels proposed by PMPRB. Price reductions of 32-99% were recommended for treatments that were approved in order to be listed for reimbursement. This review showed that the new PMPRB regulations could be creating challenges for manufacturers of rare disease treatments to meet Canadian pricing regulations. These regulations may jeopardize the launch of new medicines and limit opportunities to add to the development of real-world evidence of orphan drugs, which can be used in reimbursement approaches such as pay-for-performance.

Epidemiology of pediatric multiple sclerosis: A systematic literature review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a debilitating immune disease leading to demyelination, neurodegeneration, and chronic inflammation of the central nervous system. Pediatric MS is a rare form of the disease and effects approximately 2-10% of individuals with MS. Diagnostic criteria and therapies are continuously evolving, thus it is imperative to further understand the epidemiology and subsequently global and regional disease burden of pediatric MS. Our objective was to conduct a systematic literature review and meta-analysis to assess the incidence and prevalence of pediatric MS globally. Subgroup analyses were also conducted by region and diagnostic criteria used to ascertain cases. METHODS: A systematic literature review was conducted using searches run in EMBASE and MEDLINE. A hand search was also conducted, and the bibliographies of any relevant articles were reviewed for any studies potentially not captured by the databases. A random effects model was used to combine epidemiological estimates across studies. Subgroup analyses by region and diagnostic criteria were performed in instances when three or more studies were available for analyses. RESULTS: A total of 2,965 publications were identified, of which 187 were eligible for full-text screening. A total of 21 full-text articles met the eligibility criteria and were included for data extraction, with 18 studies included for meta-analysis. Regional epidemiologic estimates were obtained for North America, Europe, Middle East, and Asia. Country specific data was available for Canada, United States, Germany, Iceland, Netherlands, Sardinia, Slovenia, UAE/Abu Dhabi, Iran, Israel, Jordan, Kuwait, Tunisia, Taiwan, and Japan. Thirteen studies representing 12 countries reported incidence of pediatric MS. Overall incidence ranged from 0.05 to 2.85 and pooled global incidence was calculated to be 0.87 (95% CI: 0.35-1.40) per 100,000 individuals annually. Ten studies representing 10 countries reported on the prevalence of pediatric MS. Overall prevalence ranged from 0.69 to 26.92 per 100,000 individuals and pooled global prevalence was calculated to be 8.11 (95% CI: 2.28-13.93) per 100,000 people. CONCLUSION: To our knowledge, this is the first meta-analysis conducted to provide pooled estimates of incidence and prevalence estimates of pediatric MS globally. In general, incidence estimates were similar across regions; however, prevalence was found to be more variable. Noticeable gaps in evidence include a lack of pediatric MS estimates from other large regions of the world such as Africa, South America, Russia, and Australia. Moreover, there is a need for more population-based studies using the most up to date diagnostic criteria.

Saccharomyces cerevisiae Mus81-Mms4 prevents accelerated senescence in telomerase-deficient cells.

Alternative lengthening of telomeres (ALT) in human cells is a conserved process that is often activated in telomerase-deficient human cancers. This process exploits components of the recombination machinery to extend telomere ends, thus allowing for increased proliferative potential. Human MUS81 (Mus81 in Saccharomyces cerevisiae) is the catalytic subunit of structure-selective endonucleases involved in recombination and has been implicated in the ALT mechanism. However, it is unclear whether MUS81 activity at the telomere is specific to ALT cells or if it is required for more general aspects of telomere stability. In this study, we use S. cerevisiae to evaluate the contribution of the conserved Mus81-Mms4 endonuclease in telomerase-deficient yeast cells that maintain their telomeres by mechanisms akin to human ALT. Similar to human cells, we find that yeast Mus81 readily localizes to telomeres and its activity is important for viability after initial loss of telomerase. Interestingly, our analysis reveals that yeast Mus81 is not required for the survival of cells undergoing recombination-mediated telomere lengthening, i.e. for ALT itself. Rather we infer from genetic analysis that Mus81-Mms4 facilitates telomere replication during times of telomere instability. Furthermore, combining mus81 mutants with mutants of a yeast telomere replication factor, Rrm3, reveals that the two proteins function in parallel to promote normal growth during times of telomere stress. Combined with previous reports, our data can be interpreted in a consistent model in which both yeast and human MUS81-dependent nucleases participate in the recovery of stalled replication forks within telomeric DNA. Furthermore, this process becomes crucial under conditions of additional replication stress, such as telomere replication in telomerase-deficient cells.